分化抑制因子ID1在非小细胞肺癌EGFR-TKIs耐药中的作用和机制研究

The resistance of Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) is the bottleneck of targeted therapy for non-small cell lung cancer. Furthermore, the underlying mechanism is still unknown which calls for deeper research. Inhibitor of differentiation 1 ( ID1) is a transcription factor, participating in the tumorigenesis and drug resistance. With the help of the result of a National Natural Science Fundation of China ,the pre-experiment found that high expression of ID1 in TKIs resistance cells PC-9/AB2, and low expression in sensitive cells PC-9. When ID1 was over expressioned in PC-9 ,the resistance of the cells to EGFR-TKIs increased . Combined with the domestic and overseas relevant researches, we concluded that ID1 may regulate EGFR-TKIs resistance, though the mechanism is unclear. Based on the result of previous research, our new project would discuss the role of ID1 in biological function and molecular mechanism of TKIs resistance, perform the functional-complementary experiments using over expression and siRNA technology from the point of view of cells ,animals and clinical tissue. In a word, the research can improve the theory of TKIs resistance，also can offer a new thinking of antitumor drug resistance and novel targets to new medicines.

EGFR-TKIs耐药是非小细胞肺癌靶向治疗重大瓶颈，且EGFR-TKIs耐药机制不明，有待进一步深入研究。分化抑制因子1（ID1）是一种转录因子，参与肿瘤的发生发展。在前期国家自然基金项目的基础上，本项目预实验发现EGFR-TKIs耐药肺癌细胞株PC-9/AB2中ID1呈高表达，而敏感细胞株PC-9中呈低表达；如在PC-9中过表达ID1，则EGFR-TKIs耐药性增强。故推测ID1参与EGFR-TKIs耐药，但具体机制不明。在前期基础上,本项目拟用过表达与siRNA技术进行功能互补实验，从分子、细胞、动物与临床样本角度探讨ID1参与EGFR-TKIs耐药的功能，深入探讨ID1调节EGFR-TKIs耐药的分子机制，剖析ID1调节非小细胞肺癌EGFR-TKIs耐药临床规律，从而为EGFR-TKIs耐药研究提供新思路及新药筛选提供新靶点,同时可丰富并完善EGFR-TKIs耐药理论。

EGFR TKI耐药是非小细胞肺癌靶向治疗中亟待解决的重大问题。分化抑制因子 1(ID1)作为一种转录因子，在多个肿瘤的发生发展中发挥作用。本项目中，我们发现耐药肺癌细胞ID1表达增高，提示ID1可能参与了肺癌EGFR TKI耐药。随后我们利用ID1基因过表达载体以及siRNA载体转染细胞，获得了ID1基因过表达细胞以及基因沉默细胞，进一步研究显示，ID1可能通过JAK/STAT3信号途径参与了肺癌的EGFR TKI耐药。接下来的动物试验证实了ID1表达增高的肺癌对吉非替尼产生了耐药性。最后，免疫组化检测NSCLC患者的手术标本ID1的表达，统计学分析ID1表达与NSCLC患者临床病理特点以及预后的关系，发现鳞癌ID1蛋白表达显著高于腺癌，ID1的表达是NSCLC患者PFS的独立预后因子。本研究探讨了ID1 调节肺癌 EGFR TKI 耐药的分子机制，总结了ID1 调节NSCLC患者EGFR TKI耐药的临床特征，从而为 EGFR TKI靶向治疗耐药的研究提供了新思路。